Oxidative DNA damage and the mutations it causes have been implicated in a number of human diseases, including cancer and neurodegenerative diseases. Oxidative DNA damage is also a contributing factor to aging. Oxidative DNA damage results from the interaction of reactive oxygen species (ROS) with DNA. ROS are produced as by-products of normal aerobic metabolism and by exogenous factors, such as ionizing radiation and chemical oxidants. The deleterious consequences of ROS are held in check by proteins that prevent or repair oxidative DNA damage. A balance between DNA repair and damage prevention mechanisms and ROS production is required to maintain a low spontaneous mutation rate. Factors that increase ROS production, reduce ROS detoxification, or affect repair of oxidative DNA lesions can result in increased mutagenesis.